2,5-Diphenylcycloaliphatic Alkylamines

ABSTRACT

Compounds of the following formula are useful as bactericides:   WHERE   REPRESENTS A RING CONTAINING 6 CARBON ATOMS AND HAVING 0 TO 3 DOUBLE BONDS; N IS 1 OR 2; M IS 0, 1/2 OR 1; AND X is halogen, sulfate, or bisulfate. An exemplary species of the above compound is 2,5diphenylcyclohexenylmethylamine hydrochloride.

:40 7 3 64 3 541 United Sta Berezin et a1.

[ 2,5-DlPHENYLCYCLOALIPHATIC ALKYLAMINES Investors: Gilbert H. Berezin,West Chester;

260/465 R, 2 0544 4, 260/557 B, 2 9/5108 R, 260/570.9,"260/599, 106/15R, 252/110, 424/330 51 1nt.Cl. 0076 87/28 58 Field of Search 260/5709,570.5; 424/330 [56] References Cited UNITED STATES PATENTS 3,652,5893/1972 Flick et al 260/5705 Primary Examiner-Robert V. Hines Feb. 4,1975 [57] ABSTRACT Compounds of the following formula are useful asbactericides:

(CH NH (mo where represents a ring containing 6 carbon atoms and having0 to 3 double bonds; n is 1 or 2; m is 0, /2 or 1; and X is halogen,sulfate, or bisulfate.

An exemplary species of the above compound is2,5-diphenylcyclohexenylmethylamine hydrochloride.

3 Claims, No Drawings 1 2,S-DIPHENYLQYCQOALIPHATIC ALKYLAMINESBACKGROUND OF THE INVENTIQN Chemical compounds having bactericidalactivity I have been used in pharmaceutical, cosmetic, and industrialapplications. However. in recent years the use of bactericides such asthe mercurials. hexachlorophene and chlorinated phenols are beingrestricted because oftoxicity problems. Thus, there is a need for thedevelopment of new bactericides for such uses which do not have toxicityproblems.

SUMMARY OF THE INVENTION We have discovered that the compoundsrepresented by the following formula are useful bactericides:

(CH -NH '(HX) In the above formula the symbol I (orig-N11 HCl however,the exact position of the double bond in the middle ring is notpresently known. Data examined to date indicates that it probably is inthe position illustrated above, however, it could be located in theposition indicated by the dotted line.

DESCRIPTION OF THE INVENTION The compounds ofthe invention can beprepared according to the following reaction scheme which illustratesthe preparation of the preferred compound.

alkali metal hydride N C HCl I I N acrylonitrile -9 CH NH 'HCl Thestarting materials for the preparation ofthe compounds of the inventioncan be synthesized using the Diels-Alder reaction. Reaction of 1,4-diphenylbutadiene with acrylonitrile or acrolein gives2,5-diphenylcyclohexenylcarbonitrile or -carboxaldehyde, respectively.Preparation of 2,5-diphenylcyclohexane-cisand trans-carboxylic acids viathe Diels- Alder reaction is described in the literature [Ann.57l, 87(1950)]. Temperatures and times for these Diels- Alder reaction canrange from l00 to 200C. and from 10 to 30 hours. The reactions can occurwith or without solvent. If desired, solvents such as benzene, tolueneand xylene can be employed.

The double bond of 2,5-diphenylcyclohexenylcarbonitrile can beisomerized with base. Strong bases such as alkali metal alkoxides arepreferred, although other bases such as sodium amide, alkyl lithiums orsodium hydride can be used. The 2,5-diphenylcyclohexenylcarbonitrilescan then be reduced to 2,5- diphenylcyclohexenylmethylamines with analkali metal hydride, such as lithium aluminum hydride.

The 2,5-diphenylcyclohexenylcarboxaldehydes can be reduced to2,S-diphenylcyclohexenylmethanol with an alkali metal hydride, such assodium borohydride. The hydroxyl group of the alcohol can be convertedinto a leaving group such as tosylate, mesylate or brosylate by reactionwith the appropriate sulfonic acid halide, such as p-toluenesulfonylchloride. Conversion of the hydroxyl group into a halo group with ahalide acid or thionyl chloride or bromide can also be accomplished.

Salts of the free amines of this invention can be formed by contactingthe amine with the appropriate inorganic acid in a solvent and eithercollecting the salt by filtration or by evaporation of the solvent. Theamine hydrochlorides may be conveniently prepared by treating anethereal solution of the amine with dry hydrogen chloride.

The following examples illustrate the preparation of the compounds ofthe invention.

EXAMPLE No. l

2,5-Diphenylcyclohexenylmethylamine hydrochloride A mixture of 40 g(0.194 mol) of 1,4- diphenylbutadiene and 13.7 g (0.258 mol) ofacrylonitrile with l g of hydroquinone was reacted at 190C for 19 hrs.The reaction mixture was distilled to give 40 g of2,5-diphenylcyclohexenylcarbonitrile. bp 0.25 190C.

A solution of 8.8 g (33 mmol) of the above oil and 3 g (0.13 mol) ofsodium in 88 ml of ethanol was heated at reflux overnight. The reactionmixture was cooled and then concentrated in vacuum. Water was added tothe residue and the product was extracted into benzene. The organicsolution, after drying over magnesium sulfate, was concentrated to 8.7 gof oil.

The 8.7 g of oil was dissolved in 50 ml of tetrahydrofuran and addeddropwise to a stirred suspension of g (0.13 mol) of lithium aluminumhydride in 150 ml of tetrahydrofuran. The reaction mixture was refluxedovernight and then cooled. Ether was added and the excess lithiumaluminum hydride was destroyed with 20 percent aqueous sodium hydroxide.The liquid phase was decanted from the solid and the solid was washedwith THF. The combined organic liquids were concentrated in vacuum andthe residue was then dissolved in dry ether. The ether solution, afterdrying over potassium carbonate, was treated with dry hydrogen chloride.The precipitate was collected by filtration and was recrystallized fromethanol to give 2,5- diphenylcyclohexenylmethylamine hydrochloride ascolorless crystals, mp 260.

EXAMPLE No. 2

p-Terphenyl-2-methylamine Hydrochloride A solution of 2.3 g (8.4 mmol)of p-terphenyl-2- carboxamide [J. Chem. Soc., 3480 (1957)] in 25 ml ofglyme was added dropwise to a suspension of 2 g of lithium aluminumhydride in 75 ml of tetrahydrofuran and the reaction mixture wasrefluxed overnight. The excess lithium aluminum hydride was destroyedwith 20 aqueous sodium hydroxide and the liquid was concentrated invacuum. The residue was dissolved in ether, and after drying overpotassium carbonate, was treated with dry hydrogen chloride. Theprecipitate was collected by filtration to give 1.2 g of p-terphenyl-2'-methylamine hydrochloride as colorless crystals, mp 240".

EXAMPLE NO. 3

EXAMPLE NO. 4

2,5-Diphenylcyclohexane-trans-methylamine Hydrochloride A solution of g(35.7 mmol) of 2,5-

diphenylcyclohexane-trans-carboxylic acid [Ann. 571," 87 (1950)] and 43g (0.357 mol) of thionyl chloride was heated under reflux for 2 hrs.,coo1ed and then concentrated in vacuum to give the corresponding acidchloride as an oil.

The acid chloride was treated in chloroform with gaseous ammonia andthen the solvent was removed in vacuo. The residue was titurated with 10percent aquedrochloride. as colorless crystals. mp 2l0-240 dec.

EXAMPLE NO. 5

2,5-Diphenylcyclohexane-cis-methylaminc Hydrochloride2,5-Diphenylcyclohexane-cis-carboxylic acid [Ann. 571, 87 (1950)] wasconverted to 2.5- diphenylcyclohexane-cis-carboxamide mp l55-6.5.according to the procedure described in Example 4.

The amide was reduced with lithium aluminum hydride according to theprocedure described in the third paragraph of Example 1, to afford 2,5-diphenylcyclohexane-cis-methylamine hydrochloride as colorless crystals,mp 216220 dec.

EXAMPLE NO. 6

2,5-Diphenylcyclohexenylethylamine Hydrochloride A mixture of 240 g(1.165 mol) of 1,4- diphenylbutadiene and 90 g (1.6 mol) of acroleinwith 1 g of hydroquinone was reacted at 190C for 19 hrs. The reactionmixture was distilled to give 248.3 g of 2,-S-diphenylcyclohexenylcarboxaldehyde, bp,, 172C.

A solution of 20 g (76.3 mol) of the aldehyde and 4 g (0.1 mol) ofsodium borohydride in ml ofethanol was stirred overnight at room tempand then poured onto water. The product was extracted into ether, whichwas washed with water, dried over magnesium sulfate and concentrated invacuo to 19.2 g of 2,5- diphenylcyclohexenylmethanol, as a colorlessoil.

The alcohol (19.2 g, 73 mmol) dissolved in 100 ml of pyridine wastreated with 15.2 g (79.7 mmol) of ptoluenesulfonyl chloride at 0C andthen was stirred overnight at room temp. The reaction mixture was pouredonto ice-water containing ml of concentrated hydrochloric acid and theproduct was extracted into ether. The ether was dried over magnesiumsulfate and removed in vacuum to yield 26.7 g of 2,5-diphenylcyclohexenylmethanol tosylate. as a colorless oil.

A solution of 26.7 g (63.6 mmol) of the tosylate and 6 g (0.123 mol) ofsodium cyanide in 100 ml ofdimethylsulfoxide was stirred overnight atroom temp and then poured onto water. The product was extracted intoether, which was dried over magnesium sulfate and evaporated undervacuum to give 15 g of 2,5-diphenylcyclohexenylacetonitrile, as acolorless oil.

The nitrile was reduced with lithium aluminum hydride according to theprocedure described in paragraph 3 of Example 1 to give2,5-diphenylcyclohexenylethylamine hydrochloride, as colorless crystals.

UTILITY The compounds of the invention are highly effectivebactericides; they are active against a broad spectrum of bacteriaincluding gram-negative and gram-positive organisms rr t The bafctericim ofithe invention are useful in industrial applic'afions such as inadhesives, caulking compounds, cutting oil pa l llg flnd the like. Theyare also useful as bactericid r application to the skin, i.e., they canbe incorporated into cosmetics. soaps, and detergents. These utilitieswill be discussed in greater detail in the following paragraphs.

The bactericides of this invention can be used to control n icrobio logigal deterioration of oil-water emulsions. AlthouglTdil-wateremulsions can contain a wide range of bacteria, the bacteria of thegenus Pseudomonas cause the major degradation problems in manyinstances. The bactericides of this invention are active against a widevariety of bacteria including those of the genus Pseudomonas.

Oil-water emulsions are commonly encountered. For example, wet airplanefuels are often subject to microbiological degradation. In theseinstances, fouling of fuel lines and corrosion of fuel tanks can occur.The use of the compounds of this invention can reduce or eliminate thisproblem when added to the fuel in amounts from 0.0l to 1.0 percent.

Another example of an area where oil-water emulsions are widely used isin the machine tool industry. In many grinding and milling operations,cutting oils containing from 2 to l0 percent by weight oil in water areused as both lubricants and cooling agents. These cutting oil systemsare open to the air and exposed to con tamination which ranges fromairborne bacteria to waste organic matter. As the bacterial populationsin these oils increase, foul odors develop, thus shortening the usefullife of these oil-water emulsions. The bactericides of the inventionwill alleviate this problem when added to the cutting oils in amountsranging from 0.01 to 0.1 percent. (When being added to the oils thebactericides should be finely ground and then added to the oil withsufficient agitation to ensure even distribution of the material in theoil-water emulsion.

It is often desirable to grind the active bactericide to obtain a fineparticle size. This grinding can be accomplished in ball rills, sandrills, air rills, micropulverizers,

and the like.

Q liactericides are often added to paints to protect the aim while it isin the can. Thus, the bactericides can 1;; be dispersed in a f ilmformer solution or suspension in amounts ranging from 0j0Tto' l'l 0percent. The film former can be any paint, enamels, lacquers or varnish,

l' e.g., latex paints, acrylic paints, alkyd paints, vinyl acrylicpaints, alkyd modified acrylics, etc. They are particularly useful withwater base paints. The bacteriipcides canbe added to the paint bygrinding them to a "\lfine particle size and then incorporating theminto the solution or suspension with agitation.

The bactericides of the invention can also be used in cosmetics in viewof their activity against the bacteria formed on human skin.

The bactericides can be incorporated into cosmetic preparation bythoroughly mixing the finely ground bactericide with the cosmeticemulsion or by thoroughly blending with a dry powder such as a dustingpowder. The concentration of the bactericides will vary from 0.01 to 1.0percent. Examples of cosmetics wherein the bactericides can be employedare liquid deodorant colognes, hand lotions, hand creams, hairdressings, dusting powders, cream hair oil, astringent creams,astringent lotion, and deodorant cream.

Furthermore, many cosmetics are based on oil-water emulsions. Theseproducts are subjected to microbiological attack before and during use.Spoilage of the cosmetic before use renders the item unusable whilecontamination during use can cause the spread of in fections. The use ofthe compounds of this invention can also reduce or eliminate theseproblems.

The bactericides of the invention can also be used as the bactericidallyactive ingredient in a large number of soaps and detergents. The use ofsuch soaps and detergents will reduce the bacterial population of theskin.

The bactericides can be incorporated into the soaps and detergents bythoroughly mixing the finely ground compound into the soap or detergentbefore the final drying stops. The concentration of bactericides shouldrange from 0.01 to 1.0 percent.

The types of soaps which can be so treated include liquid soaps,powdered soaps, and synthetic detergents.

The following examples illustrate the bactericidal activity of thecompounds of the invention.

EXAMPLE NO. 7

The test procedure employed is the standard microbiological test tubeliquid serial dilution method for determining susceptibility toantibiotics. (Bailey, W. R., and E. G. Scott, 1962. DiagnosticMicrobiology, A Textbook for the Isolation and Identification ofPathogenic Microorganisms. The C. V. Mosby Publ. Co., St. Louis, Mo.,pp. 250253.)

The tests were conducted as follows:

Ten mg of the compounds from each of Examples I06 were mixed with 50 mlof sterile, distilled water containing 2.0 ml of dimethylformamide andone drop of Tween surfactant. Appropriate dilutions were made from thissolution in sterile distilled water,

Test compound concentrations were made by adding one ml of a dilutedsolution to 1 ml of sterile, doublestrength Difco (Difco Laboratories,Detroit, Michigan) brainheart infusion broth (without PAB) in pluggedtest tubes.

The final test concentrations of I00 mcg, 50 mcg, 10 mcg, 2 mcg and 0.4mcg of compound per ml of culture medium were aseptically inoculatedwith two drops of an overnight broth culture ofa test bacterium andincubated at 37C.

After incubation for 48 hours, the test tubes were observed for signs ofgrowth (turbidity). The lowest compound concentration tested whichinhibited the bacterial growth (tubes remained clear) was recorded inthe table as the minimal inhibitory concentration (M.I.C.).

The test results are indicated in the following table.

IN ANTIBACTERIAL ACTIVITY IN BRAIN-HEART INFUSION CULTURE BROTH M.I.C.(mcg/ml) After 48 Hours at 37C IN ANTIBACTERIAL ACTIVITY IN BRAIN-HEARTINFUSION CULTURE BROTH M.I.C. (meg/ml) After 48 Hours at 37C Compound ofEx. l Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6

Gram-Negative Bacteria Salmonella t \'pliimurium IO 50 5O 50 5O 50Escherichia IO 50 50 I00 I00 50 Pseudomonas aeruginosa l0 I00 100 I00100 I00 Pro/en: vulgaris 50 IOO 100 100 IOO 100 Klebsiella acrobat-[erI0 I00 I00 I00 100 I00 Serraliu marcescen: 50 100 l00 100 I00 I00Aerobucler cloame I0 50 O 5O 5O 5O EXAMPLE NO. 8 We claim:

A standard cutting oil, Sun Oils SECO" oil, is diluted with water togive 950 parts of a 3 percent by weight oil-water emulsion. To thisemulsion is added 50 parts ofa rancid oil. The mixture is stirred andallowed to sit for 4 to 6 weeks. Samples are taken and a colony count ismade of the bacteria present in the emulsion by the standardquantitative plate count method. The counts obtained are indicated inthe following Table.

Some of the samples are then treated with the indicated amounts of2,5-diphenylcyclohexenylmethylamine hydrochloride, the compound havingbeen finely ground with glass beads in a rill. Colony counts are thentaken at the times indicated and the results are also indicated in theTable.

l. A compound of the formula wherein hydro-

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 wherein n is 1.3. 2,5-Diphenylcyclohexenylmethylamine hydrochloride.